Air pollution particles hijack peroxidasin to disrupt immunosurveillance and promote lung cancer
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This is an interesting study that reveals a completely new mechanism by which inhaled fine particles may promote lung tumor development. The authors provide direct evidence that protein corona on those foreign objects can elicit such adverse effects. Their findings highlight the importance of the corona-endowed, 'new' bioactivity of nanomaterials in vivo - and even in a particular tissue-lungs.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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- Evaluated articles (eLife)
- Cancer Biology (eLife)
Abstract
Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM’s bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of antitumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) – an enzyme mediating type IV collagen (Col IV) crosslinking – onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8 + T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourishing of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on the tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks.
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Evaluation Summary:
This is an interesting study that reveals a completely new mechanism by which inhaled fine particles may promote lung tumor development. The authors provide direct evidence that protein corona on those foreign objects can elicit such adverse effects. Their findings highlight the importance of the corona-endowed, 'new' bioactivity of nanomaterials in vivo - and even in a particular tissue-lungs.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The hypotheses that 'Air Pollution Particles Hijack Peroxidasin' and thereby inhibit immune surveillance is striking, and of such broad and practical significance that it deserves thorough investigation. It adds to an already important set of reasons for particle inhalation be consider as promoters of cancer. The concept that the in situ adsorbed layer (protein corona) on the surface of particle can itself become an active catalyst in production of aberrant matrix is innovative. This concept as it matures could raise many new questions, for example linked to why different pollutant particles have different risks, and many other practical questions that have long eluded investigators. While this effect reported here is far from the only potential risk from such particles, it could well turn out to be a …
Reviewer #1 (Public Review):
The hypotheses that 'Air Pollution Particles Hijack Peroxidasin' and thereby inhibit immune surveillance is striking, and of such broad and practical significance that it deserves thorough investigation. It adds to an already important set of reasons for particle inhalation be consider as promoters of cancer. The concept that the in situ adsorbed layer (protein corona) on the surface of particle can itself become an active catalyst in production of aberrant matrix is innovative. This concept as it matures could raise many new questions, for example linked to why different pollutant particles have different risks, and many other practical questions that have long eluded investigators. While this effect reported here is far from the only potential risk from such particles, it could well turn out to be a significant effect, with potential to be eliminated.
The chain of logic is that (1) particles adsorb a corona of peroxidasin (PXDN) and thereby (2) proactively catalyse type IV collagen (Col IV) crosslinking, (3) thereby inducing thickening of tissue matrix and (4) hampering migration of anti-tumor immunocytes. -decreasing the mobility of cytotoxic CD8+ T lymphocytes and impairing the local immune surveillance.
The hypotheses are intriguing, and each segment of this logic is backed up by appropriate experiments. The hypothesis is so broad and far reaching, and involves so many steps, that it is challenging to fully and conclusively prove each of these points and make them unassailable. Certainly, some of the steps in the argument will require much more research in future, especially those that establish the adsorbed enzyme as the sole actor in aberrant matrix. However, rather than a point by point questioning of the strength of each argument, in my view, it is more constructive to say the authors have done enough to make the overall hypothesis credible.
It is probably important to stress that these effects are not the only ones that particles induce that may be liked to early stages of cancer, and indeed to metastases, but experts looking at this article are likely to feel that the whole question is sufficiently interesting and sufficiently argued that it should be investigated in great detail.
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Reviewer #2 (Public Review):
This manuscript focused on the bioactivity of inhaled fine particulate matter (FPM) in promoting lung tumor progression. The authors presented carefully performed work with impressive quantity. They shed light on that FPM accelerated tumorigenesis through disordering interstitial extracellular matrix in lung tissue and subsequently impairing early immune defense to tumor cells. Besides, they found that FPM's bioactivities are endowed by an unexpected enzyme, peroxidasin, related to the collagen crosslink and the latter's abnormal high enzymatic activity. These findings are promising to provide a new potential target for preventing FPM-relevant diseases.
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Reviewer #3 (Public Review):
Smoke and air pollution have been linked to lung cancer in many public health reports. While tobacco usage is associated with an increased mutational burden in lung cancer cells and thus recognized as a carcinogen, the mechanism underlying the association between air pollution and lung cancer remains unclear. In this manuscript, the authors raised a new hypothesis, that inhalable fine particulate matter (FPM) acts through the extracellular matrix to inhibit the migration of immune cells, which impairs the clearance of tumor cells. They tested the hypothesis in mouse tumor models and found that the FPM directly promoted tumor progression through selectively crosslinking type IV collagens. They further demonstrated that FPM exerted its effects by recruiting and activating peroxidasin on its surface. The …
Reviewer #3 (Public Review):
Smoke and air pollution have been linked to lung cancer in many public health reports. While tobacco usage is associated with an increased mutational burden in lung cancer cells and thus recognized as a carcinogen, the mechanism underlying the association between air pollution and lung cancer remains unclear. In this manuscript, the authors raised a new hypothesis, that inhalable fine particulate matter (FPM) acts through the extracellular matrix to inhibit the migration of immune cells, which impairs the clearance of tumor cells. They tested the hypothesis in mouse tumor models and found that the FPM directly promoted tumor progression through selectively crosslinking type IV collagens. They further demonstrated that FPM exerted its effects by recruiting and activating peroxidasin on its surface. The results of the study suggested that targeting peroxidasin may be used as a conceptually new strategy to prevent cancer.
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